Alpha,alpha,alpha,alpha&#39;,alpha&#39;,alpha&#39;-hexafluorodi-m-tolylamine derivatives

ABSTRACT

A,A,A,A&#39;&#39;,A&#39;&#39;,A&#39;&#39;-HEXAFLUORODI - M - TOLYLAMINE DERIVATIVES ARE PROVIDED HAVING THE STRUCTURE   BIS((F3C-)PHENYL)-N(-R)   WHEREIN R IS AS DEFINED HEREINAFTER. THESE COMPOUNDS ARE USEFUL AS ANTIBACTERIAL AGENTS AND IN TREATMENT OF HYPERTENSION.

US. Cl. 260-570.5 P 5 Claims ABSTRACT OF THE DISCLOSUREt,ot,0t,ot',ot',a'-HX3Jfill0l0dl m tolylamine derivatives are providedhaving the structure wherein R is as defined hereinafter. Thesecompounds are useful as antibacterial agents and in the treatment ofhypertension.

The present invention relates to a,a,a,a',a',m'-hexafiuorodi-m-tolylamine derivatives having the structure R N 136 a Go Fawherein R is or lower alkylene-NR R wherein R can be hydrogen, loweralkyl, lower alkoxy, aralkyl, monocyclic cycloalkyl, and monocyclicaryl; R and R can be the same or different and can be hydrogen, loweralkyl, aralkyl, monocyclic cycloalkyl, hydroxy-lower alkyl, orhydroxylower alkoXy-lower alkyl, and R and R can be taken together withthe nitrogen to form a 5 to 7 rnembered monocyclic heterocyclic ring;and to non-toxic acid-addition salts thereof.

The term lower alkyl as employed herein includes both straight andbranched chain radicals of up to and including eight carbon atoms, forinstance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4- trimethylpentyl and the like. The lower alkyl group can includesubstituents such as aryl.

The term lower alkoxy includes straight and branched chain lower alkylgroups attached to an oxygen.

The term monocyclic aryl as employed herein includes monocycliccarbocyclic aryl radicals, for instance, phenyl and substituted phenylradicals, including lower alkylphenyl, such as tolyl, ethylphenyl,butylphenyl and the like, di(lower alkyl)phenyl, (e.g., dimethylphenyl,3,5-diethylphenyl and the like), halophenyl (e.g., chlorophenyl,brornophenyl, and 2,4,5-trichlorophenyl) and nitrophenyl.

United States Patent 0 The term monocyclic cycloalkyl includes cyclicradicals containing from 3 to -6 ring members (e.g., cyclopropyl,cyclobutyl, cyclopentyl and cyclcthexyl).

The term lower alkylene encompasses straight chain [(CH where n is 2 to8] or branched bivalent lower alkyl groups containing from two to eightcarbon atoms.

Examples of the basic nitrogen containing radical symbolized by thegroup (II) R include amino, lower alkylamin-o, e.g., methylamino,ethylamino, di(lower alkyl)amino, e.g., dimethylamino, diethylamino,dipropylarnino, (hydroxy lower alkyl) amino, e.g., B-hydroxy ethylamino,di(hydroxy lower alkyl)amino, e.g., di(hydroxy-ethyDamino, phenyl(loweralkyl)amino, e.g., benzylamino, and phenethylamino.

As indicated above, the nitrogen may join with the groups represented byR and R to form a 5 to 7 membered monocyclic heterocyclic containing, ifdesired, an oxygen, sulfur or an additional nitrogen atom, (not morethan two hetero atoms altogether), that is, the two symbols R and Rrepresent together tetramethylene, pentamethylene, azahexamethylene,azapentamethyletne, azatetramethylene, Ithiapentamethylene orthiatetramethylene. The heterocyclic group may also be substituted byone or two groups represented by R R or R Illustrative heterocyclicgroups include piperidino, e.g., methylpiperidino, di(loweralkyl)piperidino, e.g., dimetlhylpiperidino, (lower alkoxy)piperidino,e.g., methoxypiperidino, pyrrolidino, (lower alkyl)pyrrolidino, e.g.,Z-methylpyrrolidino, di(lower alkyl)pyrrolidino, e.g., 2,5-dimethylpyrrolidino, (lower alkoxy)pyrrolidino, e.g., ethoxypyrrolidino,morpholino, (lower alkyl)morpholino, e.g., 3-methylmorpholino or2methylrnorpholino, di- (lower alkyl)morpholino, e.g.,2,3-dimethylmorpholino, (lower alkoxy)morpholino, e.g., 2- or3-ethoxymorpl1olino, thiamorpholino, (lower alkyl)thiamor-pholino, e.g.,3-methylthiamorpholino or Z-methylthiamorpholino, di- (loweralkyl)thiamorpholino, e.g., 2,3-diethylthiamorpholino or2,3-dimethylthiamorpholino, (lower alkoxy)thiamorpholino, e.g.,Z-methoxythiamorpholino, piperazino, (lower alkyl)piperazino, e.g.,4-methylpiperazino, 2- methylpiperazino, di(lower alkyDpi-perazino,e.g., 2,3- dimethylpiperazino, hydroxy-lower alkylpiperazino, e.g.,4-(Z-hydroxyethyl)piperazino, hexamethyleneimino and homopiperazino.

Preferred are those compounds wherein R is and R and R are alkyl and/orhydrogen.

Examples of compounds falling within the present invention include, butare not limited to, the following:

e re CH 8 3. /N CH3 44.

The compounds of Formula I wherein R is and R is hydrogen can beprepared by reacting an a,a,oz, a,a,a'-hexafluoro-di-tolylamine of thestructure with formic acid at a temperature within the range of fromabout 80 to about 100 C., in an oxygen-free atmosphere. The amine isemployed in a molar ratio to the acid of within the range of from about.1 1 to about 1:1. The a,e u,a,u',a-hexafluoro-di-tolylamine is known inthe art and can be prepared by the reaction of a halobenzotrifiuoride,e.g., m bromobenzotrifluoride or ochlorobenzotrifluoride, with anacylamidobenzotrifluoride, e.g., m-acetamidobenzotrifluoride orp-benzamidobenzotrifluoride, in a solvent like nitrobenzene, withpowdered anhydrous K CO and a copper catalyst, at 190-210", followed byhydrolysis of the N-acyl group.

Compounds of Formula I wherein R is and R is other than hydrogen can beprepared by acylating an aminobenzotrifluoride of the structure byreacting it with an acid anhydride of the structure or an acyl halide ofthe structure III IV A f) Compound V is reacted with ahalobenzotrifiuoride of the structure Hal FaCO I Flo-Q VII Compounds ofFormula I wherein R is -(CH ),,NR R

can be prepared by reacting an a,a,ot,oz',oc',oc'-heXafll10I0-di-tolylamine of the structure II, with a base such as a metal hydride,for example, sodium hydride, in the presence of an aprotic solvent, suchas dimethylsulfoxide, dimethylformamide, xylene, diethylbenzene, ortoluene, to form the anion reacting the anion of VII with a halide ofthe structure VIII Hal-lower alkylene-NR R wherein Hal is Cl, Br or I,in a molar ratio of II:VIII of within the range of from about 0.9:1 toabout 1:1, in the presence of an alkali metal halide, such as sodiumiodide, in an oxygen-free atmosphere.

Examples of halides of the structure VIII suitable for use in preparingcompounds of the invention include the following: dimethylaminoethylchloride, dimethylaminopropyl chloride, methylethylaminomethyl bromide,ethylisopropylaminobutyl iodide, methylamino-ethyl chloride,aminopropylbromide, methylbenzylaminopentyl chloride,cyclohexylaminoethyl bromide, hydroxyethylaminohexyl iodide,hydroxyethoxyethylaminopropyl chloride, pyrrolidinoethyl chloride,piperidinopropyl iodide, piperazinobutyl chloride, morpholinopentylbromide, thiamor-pholinohexyl iodide as well as alkylene halidescontaining substituted heterocyclics as indicated hereinbefore.

The bases of Formula I form pharmaceutically acceptable acid-additionsalts by reaction with the common inorganic and organic acids. Suchinorganic salts as the hydrohalides, e.g., hydrobromide, hydrochloride,hydroiodide, sulfates, nitrates, phosphates, borates, etc., and organicsalts as acetate, oxalate, tartrate, malate, citrate, succinate,benzoate, ascorbate, salicylate, theophyllinate, camphorsulfonate,al'kanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g.,benzenesulfonate, toluenesulfonate and the like are also within thescope of the invention. It is frequently convenient to efiect thepurification of the product by forming the acid salt. The base may beobtained therefrom by neutralization with an alkali hydroxide such assodium hydroxide and the base in turn can be transformed into adifferent salt by reaction with the appropriate acid.

The new compounds of this invention have activity upon the centralnervous system and are especially active as central nervous systemdepressants. They may be used as tranquilizers in the alleviation ofanxiety and tension states in mammals, e.g., rats, dogs or cats. Theymay be administered orally or parenterally in the form of tablets,capsules, elixirs, injectables or the like by incorporating theappropriate dosage of the base of Formula I or a physiologicallyacceptable acid addition salt thereof, e.g.,

about '1 to 50 mg, preferably about 2.5 to 15 mg./kg./ per day in two tofour divided doses, in a conventional vehicle according to acceptedpharmaceutical practice.

Furthermore, the new compounds of Formula I are useful as antimicrobialagents and may be used to combat 10 EXAMPLES 2 TO Using the procedure ofExample 1, but replacing the a,a,a,a,a',a-hexafluoro-di-m-tolylamine byinfections in animal species, such as mice, rats, dogs, 5 l/ guinea pigsand the like, due to organisms such as Trichoo-tolynamille monasvaginalis, T richomonas foetus, Staphyloccocus i flfl' 'pyl) aureus,Salmonella schottmuelleri, Klebsiella pneumoniae, f 'P' y N ProteusvuIgaris, Escherichia 0011', C. albicans or T rich0- 10 tolynamme phytanmentagrophytes. For example, a compound or there is obtained,respectively mixture of compounds of Formula I or physiologicallyacceptable acid addition salt or quaternary ammonium Example i saltthereof may be administered orally to an infected amldeanimal, e.g., toa mouse, in an amount of about 5 to 25 E p P fl' Y '(":"s" mg. per kg.per day in 2 to 4 divided doses. These may tflfiuofo-o-tolyl)fofmamldebeconventionally formulated in a tablet, capsule or elixir E p P ybcontaining about 10 to 250 mg. per dosage unit, by comamldepounding theactive substance or substances with the con- Example (m w- 'py 'W'M'N-ventional excipient, vehicle, binder, preservative, flavor, 2Ofluoro'm-tolynformamideetc., as called for by accepted pharmaceuticalpractice. EXAMPLE 6 They may also be applied topically, e.g., todermatophytosis in a guinea pig, in a lotion, salve or cream at aAceto-III-aflfl-tfifluomtohlidine concentration of about to 3 P s? byWeight A solution of 193.2 g. of m-aminobenzotrifiuoride in 3 They mayalso he s as surface dlsmfectants- About liters of water and 100 ml. ofconcd. hydrochloric acid 0.01 to 1 percent by welght of any of thesesubsta is stirred with 140 m1. of acetic anhydride at room temmay bedlsperssd on an Inert sohd or In a hqud perature. The reaction becomesexothermic and a granu- Water and PP as a dust P P They may be lar solidseparates from solution. After stirring for 20 mincofpofated also, for pIn a p other cleallslng utes the reaction mixture is cooled, and thesolid recovagent, e.g., a solid or liquid detergent, detergent comeredby filt ti to give 1503 g" f i position, for example, in generalcleaning, in cleaning fl t l idi y; about1O3 105o gig g z z i fggg orcleanmg food handhng or (B) N,N-bis(a,a,a-trifluoro-m-tolyl)acetamideThe following examples are illustrative of the invention. A suspensionof 152 g. of anhydrous potassium carbon- All temperatures are on theCentigrade scale. ate, 3.5 g. of copper bronze, 225 g. ofaC6tO-moc,oc,oc-t1ifiuorotoluidine, and 305 g. ofm-bromobenzotrifiuoride in EXAMPLE 1 2 liters of nitrobenzene is heatedunder reflux, with stirring, in an atmosphere of nitrogen for 22 hours.After cooling, the reaction mixture is filtered, and the filtrate isNN-bls'(uflfl'mfluoromtolyl)formamlde 40 concentrated in vacuo, to give273 g. of N,'N-bis(a,a,a-

trifluoro-m-tolyl)acetamide, M.P. about 7374. A solution of 8 g. of cm,it,',a',a'-hexafiuoro-di-m-tolylamine in ml. of 9s-100% formic acid isheated at EXAM'PLES 7 To 18 with stirring, in an atmosphere of nitrogen,for 4 Using the procedure of Example 6 but substituting the hours. Theexcess formic acid is removed in vacuo, and 45 a,a,a-trifluorotoluidineshown in column 1 of Table I bethe residue is recrystallized frompentane to give 6.8 g. low and the acylating agent shown in column 2,and the of N,N-bis-(a,a,a-trifluoro m tolyl)formamide, M.P.halo-a,a,a-trifluorotoluene shown in column 3, the product about 63-65shown in column 4 is obtained.

TABLE I Column 1 Column 2 Column 3 Column 4 EX. Halo-0,01,0- No.a,u,a-trifiuoroto1uidlne Acid anhydride trifluorotoluene Product 7 CF;(")/O\(fi a (I? C2H5-O C-CzHn C-CzH; NH: Cl

(FF: I a

8 H O 0 0 B (H) N cam-(y t i-oam r 00,111 FIG CFQ I CFa -CF;

9 O O 0 c1 (H) F80 CH5(L/ ii-cm com --CF| I 13 EXAMPLE 19 III A solutionof 271 g. of N,N-bis(a,u,a-trifiuoro m- 65, recrystallization from 200ml. of diethyl ether gives 6.6 g. of product, M.P. about 65-66 (dec.).

Example 20 tolyl)acetamide in 3 liters of 95% ethanol and 800 ml. 5 y P-3 y of concentrated hydrochloric acid is heated under reflux dlamlne,hydf0ch101ld6 with stirring for 3 hours. The reaction mixture is con- ASolution of 18 g. of u,a,uu',a',ut, hexafluomdi m centrated m vacl'lolthe resldue 1S taken up 111,600 1111- of tolylamine in 120 ml. ofdimethyl sulfoxide is stirred at ether washffd Wlth of water h Wlth roomtemperature under nitrogen and 5 g. of sodium of 2 sodlum hrdroxlde, ande} W Waterhydride 50% in mineral oil) in added in small incredryufg thesfolvent removed by dlstlnatlon and the P ments over a period of 45minutes. The reaction tempera- P 1S fiaCUOHPted m vacllo to Yleld 143 off ture increases spontaneously to 38. Following the addig about tion thereaction temperature is gradually increased to 50". After minutes at 50the reaction mixture is I 15 l d to and 10 of dimeth la inoeth lchloride B NN-dlmeth 1-N,N-bls -trlfluoro-m-tol l F e g y m y i g gf y)1s added. The reaction mixture is heated 85-90 for 2 hours. Aftercooling to room temperature 5 ml. of 95 A solution of 9 g. ofOt,d,0,OL',0L',OL heXafiuOrOdi-Hl-tOlYlethanol is added. The reactionmixture is poured with amine in 60 ml. of dimethyl sulfoxide is stirredat room stirring into 1200 ml. of cold water. The oil whichsepatemperature under nitrogen and 2.5 g. (0.05 mole) of 20 rates fromsolution is extracted into ether, the solution is Sodium hydride inmineral is d d in Small Washed with water, dried, and the solventremoved. The increments over a period of minutes. The reaction residue,19 g., is taken up into 300 m1. of ether. The emperature i r aspontaneously Following ethereal solution is extracted with 200 m1. of2% hydrothe addition the reaction temperature is gradually inchloricacid, the ether is dried, filtered, and taken to drycreased to After 15minutes at 50 the reaClion 25 mess. The residue of 20.6 g. crystallizes.After trituration mixture is cooled to 30 and 30 m of 2 N dimethylwith200 ml. of diisopropyl ether the solid is filtered to aminopropylchloride in toluene is added followed by 0.5 i 9 of Solid, 12 125 ((1%),It is recrystap of Sodium iodide- The reaction miXfllIe is heated atlized from acetonitrile-ether to give 6.3 g. of product, -75 for fourhours. After cooling to room temper- 30 M P bout131 133 (Cl ature 7 ml.of ethanol is added. The reaction mixture is poured with stirring into700 ml. of ice-water. The oil Examples 45 which separates from solutionis extracted into 400 m1. Using the procedure of Example 19, butsubstituting of ether. The ethereal solution is washed with water andthe a,a,a,a',d',u, hexafluorodi-tolylarnine shown in colextracted withm1. of 2.5% hydrochloric acid. The umn 1 of Table II below and theaminoalkylene halide ethereal mother liquor is taken to dryness andtriturated 35 shown in column 2 of Table II, the product shown in withdiisopropyl ether to give 10 g. of solid, MP. 63- column 3 is obtained.

TABLE II Column 1 Column 2 Colu n 3 Ex.N0.a,a,a,a',lz,a-Hexafluoro-tolylamiue Ha1-1oweralkylene-NIVR Product 21 F0 CF Ca u 06H C1(CH )4N (CH:)4-N

CH3 CH3 F30 N O 01% CF 0 H 22 u a 4 a 2)a n 4 n H Br(CHa)a-Na l FaG- N lCH3 Fae- N- 23 11% I-(CHg)z-NH1 (ICHZIMNHA F o 0 CF 0 N Fac CF:

24 CF; (FF: CH3 (311s E (ll-OHz-CH-CHrNH: CHg-GHOH:NH:

CF; CF;

TABLE I1C0ntinued Column 1 Column 2 Column 3 EX. N o.a,a,a,a',a.,a-Hexafluoro-tolylamine Hal-lower aIkylcne-NR R Product 43 Hw j N Cl(CH2)3-N (CH2)3N I FsC CFa N FaC- CFa 44 H C1115 C2115 FaC N CFa(3H3 ({JH:

BICHCH2N O CHCH1N FaC- N- CF:

45 ('71 )CH3 OH:

H N C1(CH2)4N S (CHn)4N S O t CF; FaC- OH; Ha

FIG

EXAMPLE 46 3. Compounds in accordance with claim 1 having the Bysubstituting 161 g. of o-aminobenzotrifluoride for them-aminobenzotrifluoride and 122.5 g. of N-propyl chlorocarbonate for themethyl chlorocarbonate in Example 47, there is obtained n-propylo-(a,u,ot-trifluorotolyl)carbamate which is reacted with ahalobenzotrifluoride in accordance with Example 6 to give the abovetitled compound.

What is claimed is:

1. Compounds of the structure lower alkylene-NR R wherein R and R can bethe same or different and are selected from the group consisting ofhydrogen, lower alkyl, aralkyl, monocyclic cycloalkyl, hydroxy-loweralkyl and hydroxy-lower alkoxy-lower alkyl, and pharmaceuticallyacceptable acid-addition salts thereof.

2. Compounds in accordance with claim 1 having the structureCHzOHz-N(CH3)2 structure 4. Compounds in accordance with claim 1 havingthe structure 5. Compounds in accordance with claim 1 having thestructure (CHM-(CH3):

References Cited UNITED STATES PATENTS 2,739,984 3/1956 Hafliger260-570.5 2,687,414 8/1954 Cusic 260-243 2,889,328 6/1959 Sherlock etal. 260570.5 X

OTHER REFERENCES Yale, Journal of Med. Chem., vol. 1, No. 2, pp. 121,-126, and 131-132 (1959).

ROBERT V. HINES, Primary Examiner US. Cl. X.R.

252-106; 260-239 B, BC, 243 B, 247.5 R, 268 R, 294.7, 326.5 L, 326.85,343.7, 471 C, 501.1, 501.21, 558 R, 562 P; 424330 a v y SHOULD BE: F cNV a Patent No. 3 712 92 l Dated January 2 3 1973 Invantor(s) HarryLOulS Yale It is certified that error a and that said Letters Patent areColumn 2, line 27 I after "methylene," insert the followinghexamethylene, oxapentamethylene,

oxatetramethylene,

ppears in the above-identified patent hereby corrected as shown below:

Column 14 Example 22, formula in column 3 reads I Column 16,- Example30,, formula in column 3 the 'bond between the nitrogen atom and thesubstit is missing, please insert.

uted benzine ring Column 17 Example 34 formula in column .1, reads:

. CF V 3 F Signed and sealed this 3rd day of July 1973. v

(SEAL) Attest:

"EDWARD M.FLETCHER,JR. "AttestingiOfficer Rene Tegtmeyer ActingCommissioner of Patents

